Celia Lai

1
Vitamin C and the CNS
April 2, 2008

• Celia Lai
• celia.lai_at_utoronto.ca
• Vincci Leung
• vwc.leung_at_utoronto.ca
• Wanda Szto
• w.szto_at_utoronto.ca
• Anjie Yang
• anjie.yang_at_utoronto.ca

2
Vitamin C

• Water soluble
• Hexonic sugar acid
• Refers to both ascorbic acid (AA) and
  dehydroascorbic acid (DHA)
• Ascorbate is synthesized in the liver/ kidney
  (rodents) OR obtained from diet (humans)
• Main Sources
• Organ meats, fresh fruits, vegetables

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Quick Anatomy Review

• CNS Central Nervous System
• Brain
• Spinal Cord
• Astrocytes
• Glial cells in the CNS that provide support to
  neurons and are critical to the formation of the
  BBB
• Neurons
• specialized cells in the nervous system that
  communicate via electrochemical signals

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Ascorbate Functions

• Antioxidant
• High reducing power
• Free radical scavenger
• Donates electrons
• Enzyme co-factor
• collagen hydroxylation, carnitine synthesis,
  hormone and amino acids synthesis
• Neuromodulator in the brain
• NT receptors, functions of neurons, myelin and
  glial cell synthesis

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Functions (CNS)

• Role in catecholamine synthesis
• Noradrenaline, adrenaline (Tyrosine metabolism)
• Maturation of neurons and astrocytes

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Functions (CNS)

• Catecholamine synthesis
• Cofactor in converting DOPAMINE to NORADRENALINE
  (NE) with the enzyme dopamine-b-hydroxylation and
  subsequently to ADRENALINE (E)
• NE and E are both part of the flight and fight
  response (sympathetic nervous system)

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Functions (CNS)

• Maturation of neurons and astrocytes
• When ascorbic acid was added to precursor cells,
  it enhanced differentiation into neurons and
  astrocytes and increased post synaptic activity
• In comparison to control (no AA), cells cultured
  in the presence of AA were more mature
• AA up regulates the expression of a Notch
  (specific for astrocyte differentiation) and BMP2
  (differentiates both)

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Functions (CNS)

• Maturation of neurons and astrocytes

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Functions (CNS)

• In the brain, ICAA gt ECAA with the help of SVTC2
  
• SVTC2 are expressed in the axons of matured
  hippocampal neurons
• Deficiency in SVTC2 in hippocamal neurons leads
  to
• Shunted growth (fewer dendritic branches and
  reduced length)
• Less glutamate receptor clustering (AMPA)
• Oxidative damage

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Absorption and Storage

• Ascorbate has highest concentration in the brain,
  spinal cord and adrenal gland
• In the brain
• Blood ? CSF
• Active Na-dependent transport (SVCT2) at the
  choroid plexus
• ascorbate changes from 50mm to 500mm
• CSF ? ECF
• Simple diffusion across brain capillaries at the
  bloodbrain barrier
• ascrobate in the extracellular fluid typically
  ranges from 200mm to 400mm

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Absorption and Storage

• Take-up by Neurons
• Transported via SVCT2
• ascorbate 10mM
• Take-up by Glia
• Do not have detectable levels of SVCTI or SCVT2
• Mechanism is unknown
• ascorbate 1mM
• Regulation of level in the extracellular
  ascorbate concentration
• Level is regulated homeostatically in the brain
• Also modulated dynamically by heteroexchange of
  ascorbate with glutamate

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Absorption and Storage

• Distribution of Vitamin C in the CNS
• Higher levels in anterior regions (e.g. cerebral
  cortex) vs. lower levels in posterior regions
  (e.g. brainstem)
• ?Reflects that ascorbate present in higher
  concentration in neuron- rich gray matter than in
  white matter
• Variation in neuron-to-glia ratio in tissues

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Absorption and Storage

• Implication of absorption and distribution
  pattern
• High levels of ascorbate SVCT2 transporter in
  different neuronal cell types suggest functions
  in addition to serving as an enzyme co-factor
• 10x difference in ascorbate levels in neurons
  glia correlates with 10x oxidative metabolism in
  neurons than in glial cells Vitamin C as an
  intracellular antioxidant

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Application to Pharmacy

• Currently only approved by Health Canada for
  treatment/prevention of scurvy, use in TPN and
  slowing age-related macular degeneration (500 mg
  combination therapy)
• Increased demand in smokers, pregnant women,
  wounded

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Application to Pharmacy

• High doses kidney stones, diarrhea
• In pregnancy nenonates with scurvy!!
• Drug interactions
• Evaluate vitamin C deficiency for patients taking
  salicylates (inhibit uptake by leukocytes and
  platelets)
• False negative urine glucose tests for diabetic
  patients

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Possible Future Therapeutic Uses

• Primarily antioxidant properties (in vivo
  studies)
• Possible candidate supplement against stroke?
• Rat Brain Mitochondria study
• Primate cerebral ischemia studies
• Lowers damage from drug toxicity?
• Derivatives decreased toxicity induced behaviour
  from high doses of methamphetamine and lethality
  from methamphetamine/morphine combination in mice
• Buffers brain damage from lead toxicity (rats)
• However results are still conflicting and further
  studies are required

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Summary

• Vitamin C is a water soluble vitamin (found
  primarily in organ meats, fruits and vegetables)
  that has the ability to donate electrons
• Some of the functions of AA in the brain include
  
• Being a cofactor in the synthesis of 2 hormones,
  noradrenaline and adrenaline
• Enhancing the differentiation and maturation of
  neurons and astrocytes
• Ascorabte enters the CNS via active transport at
  the choroid plexus
• Ascorbate is subsequently distributed the CNS via
  cerebrospinal fluid
• Ascorbate is taken up by the brain cells from the
  ECF (cerebrospinal fluid)
• There are regional variations in ascorbate levels
  (e.g. glia vs. neurons)
• Currently in pharmaceutical practice vitamin C is
  used primarily to treat scurvy and also
  age-related macular degeneration
• Possible use of vitamin C is alleviating brain
  damage due to stroke or poisons are still being
  explored

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References

• CPhA Monograph. (2007). Vitamin C. e-CPS.
  http//www.e-therapeutics.ca
• Davies, MB. (1991). Vitamin C Its Chemistry and
  Biochemistry. Cambridge, UK Royal Society of
  Chemistry.
• Food and Nutrition Board. (2000) Dietary
  Reference Intake for Vitamin C, Vitamin E,
  Selenium and Carotenoids. Washington, DC
  National Academy Press.
• Lang, RS. (2004). Clinical Preventative Medicine,
  2nd edition. Chicago American Medical
  Association Press.
• Lee JY. (2003). Ascorbate-Induced Differentiation
  of Embryonic Cortical Precursors Into Neurons and
  Astrocytes. Journal of Neuroscience Research. 73
  (2) 156-165
• Qiu S. (2007). Ascorbate Transport by Primary
  Cultured Neurons and Its Role in Neuronal
  Function and Protection Against Excitotoxitiy.
  Journal of Neuroscience Research. 85
  (5)1046-1056.
• Ranjan A. (1993). Ascorbic acid and focal
  cerebral ischaemia in a primate model. Acta
  Neurochirurgica, 123 (1-2), 87-91.
• Rice, ME. (2000). Ascorbate regulation and its
  neuroprotective role in the brain. Trends in
  Neurosciences, 23 (5), 209-216.
  (http//www.sciencedirect.com/science/article/B6T0
  V-405SNMS-8/2/4a13d6ce5f202cd3c28335112de851a7)
• Sciamanna MA. (2003). Ischemia/reperfusion-induced
  injury of forebrain mitochondria and protection
  by ascorbate. Archives of Biochemistry and
  Biophysics, 305 (2), 215-224.
• Shinobu I. (2007). Differential effects of the
  ascorbyl and tocopheryl derivative on the
  methamphetamine-induced toxic behavior and
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  (http//www.sciencedirect.com/science/article/B6TC
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